The overall aim of this application is to describe the ocular response to various constituent chemicals of marijuana. These chemicals include both cannabinoids and newly identified water soluble compounds, of which the latter are highly effective in reducing intraocular pressure. The studies will be conducted on both in vitro ciliary epithelum and on in vivo rabbits and primates. The in vitgro studies will examine the effects of those cannabioids found effective in reducing intraocular pressure and the most effective water soluble compounds on both the fluid permeability and bicarbonate fluxes inthe isolated ciliary epithelium. This will allow the discrimination between specific and non specific effects at the membrane level without interference from the other factors affecting lintraocular pressure in the living eye. Pharmacological intervention will identify the locus of drug action, using either metabolic inhibitors, specific inhibitors oa anion exchange or fatty acids to modify the membrane per se. In vivo studies will determine structure-activity relationship of cannabinoids relative to intraocular pressure reduction and determine the site of action using jfluorimetry and outflow facility kmeasurements. Those compounds most active in rabbit will be further tested in primates with measurements of intraocular pressure, fluorimetry and outflow facility. The water soluble compounds will be tested in rabbits to determine the most active of the over 70 compounds thus far identified and the effects of the most active compounds in primates will be determined. The structural requirements of the molecules for induction of a afall in intraocular pressure will be identified, and fractionation of the molecules will be undertaken to seek smaller component molecules which retain the capability of reducing intraocular pressure. These studies, on both groups of chemicals from marijuana, will provide a basis for expansion of studies using the active compounds in man as potential antiglaucoma medications. Glaucoma is the third leading cause of blindness in the US and the proposed studies may provide another medial approach to reduce the elevated intraocular pressure which characterizes this disease.